Disruption of the AMPK-TBC1D1 nexus increases lipogenic gene expression and causes obesity in mice via promoting IGF1 secretion
Disruption of the AMPK-TBC1D1 nexus increases lipogenic gene expression and causes obesity in mice via promoting IGF1 secretion
复制标题
AMPK-TBC1D1 连接的破坏会增加脂肪生成基因的表达，并通过促进 IGF1 分泌导致小鼠肥胖
DOI：
10.1073/pnas.1600581113
复制
发表时间：
2016-06-28
影响因子：
11.1
通讯作者：
Chen, Shuai
中科院分区：
文献类型：
--
作者：
Chen, Liang;Chen, Qiaoli;Chen, Shuai
tre2 /USP6, BUB2， cdc16结构域家族成员1 （TBC结构域是GTPase激活蛋白结构域）（TBC1D1）是一种Rab GTPase激活蛋白，在响应细胞内能量应激时被amp激活蛋白激酶（AMPK）在Ser（231）上磷酸化。然而，这种磷酸化事件在体内的作用和重要性尚不清楚。为了解决这个问题，我们建立了一个携带TBC1D1Ser(231)Ala敲入蛋白（KI）突变的小鼠模型，并发现KI小鼠在正常的食物饮食中发生肥胖。从机制上讲，TBC1D1位于胰岛素样生长因子1 （IGF1）储存囊泡上，KI突变以依赖rab8a的方式增加内分泌和分泌旁/自分泌IGF1。IGF1的高分泌通过激活脂肪组织中哺乳动物雷帕霉素靶蛋白（mTOR）通路的蛋白激酶B （PKB，也称为Akt）导致脂肪生成基因的表达增加，随着KI小鼠年龄的增长，这有助于肥胖、糖尿病和肝脂肪变性的发展。总之，这些发现表明AMPK-TBC1D1信号通路通过IGF1分泌与PKB-mTOR通路相互作用，从而控制脂肪组织中脂质基因的表达。这些发现也对研发对抗肥胖的药物有启示。
Tre-2/USP6, BUB2, cdc16 domain family member 1 (the TBC domain is the GTPase activating protein domain) (TBC1D1) is a Rab GTPase activating protein that is phosphorylated on Ser(231) by the AMP-activated protein kinase (AMPK) in response to intracellular energy stress. However, the in vivo role and importance of this phosphorylation event remains unknown. To address this question, we generated a mouse model harboring a TBC1D1Ser(231)Ala knockin (KI) mutation and found that the KI mice developed obesity on a normal chow diet. Mechanistically, TBC1D1 is located on insulin-like growth factor 1 (IGF1) storage vesicles, and the KI mutation increases endocrinal and paracrinal/autocrinal IGF1 secretion in an Rab8a-dependent manner. Hypersecretion of IGF1 causes increased expression of lipogenic genes via activating the protein kinase B (PKB; also known as Akt)-mammalian target of rapamycin (mTOR) pathway in adipose tissues, which contributes to the development of obesity, diabetes, and hepatic steatosis as the KI mice age. Collectively, these findings demonstrate that the AMPK-TBC1D1 signaling nexus interacts with the PKB-mTOR pathway via IGF1 secretion, which consequently controls expression of lipogenic genes in the adipose tissue. These findings also have implications for drug discovery to combat obesity.